Project Summary/Abstract According to the latest estimates, over 1 in 7 Americans will develop an Alcohol Use Disorder (AUD) over the course of their lifetime, and alcohol consumption is involved in nearly 4% of deaths worldwide. Thus, AUDs represent a significant public health concern. Currently, the best pharmacotherapies for AUDs require the treatment of 10 patients to observe 1 patient reduce drinking to healthy levels. For this reason, one appealing option is to identify at-risk individuals before they become heavy drinkers; for instance a family history of alcoholism is currently among the best predictors of AUD. Adolescence presents an ideal period to study these factors as it precedes the onset of AUDs but is also a time when there is a rapid increase in consumption. We have recently shown that neuroimaging measures can be used to predict clinically meaningful outcomes (e.g. relapse), suggesting it would also be possible to develop neuroimaging as a predictor of onset of heavy drinking in adolescents. Developing predictive tools to identify adolescents likely to progress to heavy drinking would offer the opportunity for early intervention and could potentially reduce the progression to AUD. Substantial evidence suggests that primary motives for problematic drinking are to enhance positive valence and reduce negative valence emotions. Further, substance use disorders are associated with altered activity in the insula, ventral striatum, amygdala, and anterior cingulate cortex when processing potential rewards and aversive outcomes. We hypothesize that individuals at risk for AUDs will show heightened response to aversive stimuli in the anterior insula and amygdala and heightened response to rewarding stimuli in the ventral striatum and anterior cingulate cortex. We further hypothesize that they will exhibit diminished functional connectivity between reward, salience, and executive control networks. To test this, we will recruit 70 adolescents aged 18?20. Half will be have a biological parent with an AUD. The other half will be a control group matched on current drinking levels, age, gender, ethnicity, and socioeconomic status. All participants will undergo a functional MRI scan with a resting state run and a run during a modified version of the monetary incentive delay task that includes the risk of hearing an aversive sound (i.e. a loud scream). All participants will be followed for 6 months after the scan to determine levels of drinking. This study will provide both mechanistic information on risk for AUD as well as a tool to identify adolescents at greatest risk prior to the onset of problem drinking. This information could help provide personalized information about risk that may maximize likelihood of AUD prevention. In addition to the research goals described above, this is a training proposal that is designed to facilitate the transition of the primary investigator, Dr. Joshua Gowin, from mentored post-doctoral research fellow to independent, tenure-track research faculty at an academic institution. The mentored phase of the proposal will use a multifaceted training plan to improve Dr. Gowin?s knowledge base as well as his research and professional skillsets. Specifically, Dr. Gowin will learn new techniques in resting state functional connectivity analysis and in the cognitive neuroscience of emotion regulation. In addition to this scientific training, Dr. Gowin will gain experience management, teaching, and data presentation. To achieve these goals, Dr. Gowin has assembled a team of advisors from the intra- and extramural community with expertise in these areas to guide his training and development. This committee will include Dr. Vijay Ramchandani-NIAAA, Dr. Monique Ernst-NIMH, Dr. Elliot Stein-NIDA, and Dr. Susan Tapert-UCSD (see letters of support). The skills that will be developed during the mentored phase will position Dr. Gowin for success as he applies for an independent position and establishes his own research program.